ORGANIC LETTERS
Synthesis of Enantiopure Dehydropiperidinones from r-Amino Acids and Alkynes via Azetidin-3-ones
XXXX Vol. XX, No. XX 000–000
Naoki Ishida, Tatsuya Yuhki, and Masahiro Murakami* Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
[email protected] Received June 14, 2012
ABSTRACT
Chiral dehydropiperidinones were synthesized in enantiopure form from R-amino acids and alkynes via azetidin-3-ones.
Substituted piperidines are found in numerous natural alkaloids, pharmaceuticals, and agrochemicals as a privileged structural motif.1 Although a wide variety of methods for their synthesis have been developed,2 new pathways leading to their enantiopure forms starting from readily available substances are still in demand. We now report the synthesis of chiral dehydropiperidinones3 in enantiopure form from R-amino acids and alkynes via azetidin-3-ones (eq 1).4
We previously reported the nickel-5 and rhodiumcatalyzed6 insertion of alkynes and alkenes into carbon (1) (a) Escolano, C.; Amat, M.; Bosch, J. Chem.;Eur. J. 2006, 12, 8198. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. (c) Chemler, S. A. Curr. Bioact. Compd. 2009, 5, 2. (2) For recent examples of enantioselective synthesis of substituted piperidine derivatives, see: (a) Stead, D.; Carbone, G.; O’Brein, P.; Campos, K. R.; Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010, 132, 7260. (b) Beng, T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010, 132, 12216. (c) Cui, L.; Li, C.; Zhang, L. Angew. Chem., Int. Ed. 2010, 49, 9178. (d) Seki, H.; Georg, G. I. J. Am. Chem. Soc. 2010, 132, 15512. (e) Nadeau, C.; Aly, S.; Belyk, K. J. Am. Chem. Soc. 2011, 133, 2878. (f) Seel, S.; Thaler, T.; Takatsu, K.; Zhang, C.; Zipse, H.; Straub, B. F.; Mayer, P.; Knochel, P. J. Am. Chem. Soc. 2011, 133, 4774. (g) Wong, H.; Garnier-Amblard, E. C.; Liebeskind, L. S. J. Am. Chem. Soc. 2011, 133, 7517 and references cited therein. (3) For synthesis of dehydropiperidinones, see: (a) Cassldy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029. (b) Donohoe, T. J.; Fishlock, L. P.; Basutto, J. A.; Bower, J. F.; Procopiou, P. A.; Thompson, A. L. Chem. Commun. 2009, 3008. (c) Husain, I.; Saquib, M.; Bajpai, V.; Kumar, B.; Shaw, A. K. J. Org. Chem. 2011, 76, 8930.
carbon single bonds of cyclobutanones to construct complex carbocyclic skeletons. This straightforward synthetic strategy based on carbon carbon bond activation7 significantly improved the step as well as atom economies of the synthesis of chiral benzobicyclo[2.2.2]octenones.5d On the basis of these results, we next directed our attention to azetidin-3-ones, which were readily synthesized in enantiopure form from R-amino acids according to Seebach’s method (Scheme 1).8 For example, commercially available N-Boc-(L)-alanine was treated with ethyl chloroformate/triethylamine, and subsequently (4) During preparation of this manuscript, Aı¨ ssa and Louie independently reported a closely related nickel-catalyzed reaction, giving achiral dehydropiperidinone using nonsubstituted azetidin-3-ones except for one example: (a) Ho, K. Y. T.; Aı¨ ssa, C. Chem.;Eur. J. 2012, 18, 3486. (b) Kumar, P.; Louie, J. Org. Lett. 2012, 14, 2026. (5) (a) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2005, 127, 6932. (b) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2006, 128, 2166. (c) Ashida, S.; Murakami, M. Chem. Commun. 2006, 4599. (d) Liu, L; Ishida, N.; Murakami, M. Angew. Chem., Int. Ed. 2012, 51, 2485. (6) For rhodium-catalyzed alkene insertion reactions into cyclobutanones, see: (a) Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124, 13976. (b) Matsuda, T.; Fujimoto, A.; Ishibashi, M.; Murakami, M. Chem. Lett. 2004, 33, 876. (7) For reviews on transition-metal-catalyzed cleavage of carbon carbon bonds: (a) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 1. (b) Kondo, T.; Mitsudo, T. Chem. Lett. 2005, 34, 1462. (c) Necas, D.; Kotora, M. Curr. Org. Chem. 2007, 11, 1566. (d) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (e) Winter, C.; Krause, N. Angew. Chem., Int. Ed. 2009, 48, 2460. (f) Seiser, T.; Cramer, N. Org. Biomol. Chem. 2009, 7, 2835. (g) Murakami, M.; Matsuda, T. Chem. Commun. 2011, 47, 1100. (h) Aı¨ ssa, C. Synthesis 2011, 3389. (8) (a) Podlech, J.; Seebach, D. Helv. Chim. Acta 1995, 78, 1238. (b) Wang., J; Hou, Y.; Wu, P. J. Chem. Soc., Perkin Trans. 1 1999, 2277. 10.1021/ol3016447
r XXXX American Chemical Society
Scheme 1. Synthesis of Azetidin-3-ones
with diazomethane, to afford the diazomethyl ketone. Upon treatment of this species with dimeric rhodium(II) acetate, cyclization spontaneously occurred with the release of molecular nitrogen to furnish azetidin-3-one 1a with stereochemical integrity. The azetidinone 1a thus obtained was next reacted with 4-octyne (2a, 1.5 equiv) in the presence of Ni(cod)2 (5 mol %) and PPh3 (10 mol %)9 in toluene (eq 2). The insertion of 2a between the carbonyl carbon and the R-methylene carbon successfully took place at 80 °C to afford (S)-R-methylpiperidinone 3a in 73% isolated yield. Analysis of 3a by HPLC verified that the stereochemical integrity was retained again. Compound 4, the isomer possibly arising from insertion between the carbonyl carbon and the other R-carbon having a methyl substituent on it, was not formed.
Thus, the single bond between the carbonyl carbon and the R-methylene carbon was site-selectively cleaved, and the carbon carbon triple bond was inserted therein. We assume the mechanistic pathway shown in Scheme 2, which involves oxidative cyclization on nickel(0),10,11 as in the case of cyclobutanones.5a Initially, the carbonyl group of azetidin-3-one 1a and alkyne 2a are coupled on nickel(0) to afford spirocyclic oxanickelacyclopentene A, which possesses two kinds of strained carbons located γ to nickel, (9) The use of NHC and other phosphine ligands including PCy3, which was the ligand of choice for the reaction of cyclobutanones, gave a lower yield. (10) For nickel-catalyzed reactions through oxidative cyclization between unsaturated hydrocarbons and carbonyl compounds, see: (a) Modern Organonickel Chemistry; Tamaru, Y., Ed.; Willey-VCH: Weinheim, Germany, 2005. (b) Ikeda, S. Angew. Chem., Int. Ed. 2003, 42, 5120. (c) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890. (d) Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem. Commun. 2007, 4441 and references cited therein. (11) For direct observation of oxidative cyclization of carbonyls with alkenes, see: Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am. Chem. Soc. 2004, 126, 11082. B
Scheme 2. Plausible Mechanism
i.e., a methylene carbon and a methyl-substituted carbon. Whereas both are potentially amenable to migration onto nickel by β-elimination, the methylene carbon selectively migrates, probably due to steric reasons. As a result, the two rings are merged to expand into seven-membered nickelacycle B.12 Finally, reductive elimination gives six-membered ring product 3a with regeneration of the nickel(0) catalyst. Various dehydropiperidinones were synthesized in an analogous manner to 3a (Table 1). First, N-Boc- and N-Cbz-azetidin-3-ones 1b 1e were prepared in enantiopure form from the corresponding R-amino acids, i.e., phenylalanine, valine, lysine, and methionine respectively, by Seebach’s method.8 When subjected to the nickel catalysis, they all underwent alkyne insertion without any difficulties which the presence of the amino and thio functionalities might potentially bring forth. The corresponding piperidinones 3b 3e were obtained in moderate to good isolated yields (entries 1 4). Stereochemical integrity was retained with 1c derived from valine, whereas a very slight but measurable racemization was detected with 1b, 1d, and 1e. Unsubstituted achiral azetidin-3-ones 1f h13 also underwent the insertion reaction. In addition to carbamate-type N-protective groups, benzhydryl and p-toluenesulfonyl groups were also suitable for the nitrogen substituent (entries 5 and 6). Whereas PPh3 was the choice of ligand with carbamates 1a e,h and sulfonamide 1g, the use of more electron-donating PCy3 gave better results with benzhydryl-protected azetidin-3-one 1f. Good to high regioselectivities were observed with unsymmetrical alkynes 2b e. The bulkier tert-butyl and phenyl groups were placed selectively at the β-position (entries 2 and 7). This regioselectivity is explained based on sterics; when undergoing oxidative cyclization, the sterically demanding ketonic carbonyl carbon prefers to couple with the sp carbon attached to a less bulky substituent. Unlike the previous case with cyclobutanones,5a it was possible to insert alkynylstannanes 2d and 2e to give 2-stannylpiperidinones exclusively (12) For related reactions involving β-carbon elimination of spirocyclic metalacycles, see: (a) Murakami, M.; Takahashi, K.; Amii, H.; Ito, Y. J. Am. Chem. Soc. 1997, 119, 9307. (b) Matsuda, T.; Tsuboi, T.; Murakami, M. J. Am. Chem. Soc. 2007, 129, 12596. See also ref 5. (13) An azetidinol to be oxidized to 1f, N-H azetidinol hydrochloride to be derivatized to 1g, and azetidin-3-one 1h itself are commercially available. Org. Lett., Vol. XX, No. XX, XXXX
Table 1. Insertion of Alkynes into Azetidin-3-onesa
(entries 8 10). The selectivity observed with 2d and 2e can be ascribed to the less electronegative nature of tin, which renders its R-carbon to be charged negatively. The positively charged carbonyl carbon prefers to couple with the negatively charged R-carbon rather than with the βcarbon.14 The stannyl group thus set at the 2-position regioselectively could serve as the synthetic basis for allowing further carbon carbon bond formation (vide infra). In contrast, less imbalanced unsymmetrical alkyne 2f (R2 = Me, R3 = i-Pr) afforded a mixture of regioisomers (entry 11). Terminal alkynes such as 1-octyne and phenylethyne failed to participate in the insertion reaction because of their facile self-oligomerization. Thus, the present insertion reaction renders it possible to derive dehydropiperidinones with various substituents, even containing functionalities, from natural R-amino acids. Further derivatization of the enantiopure products demonstrated their synthetic utility. Reduction of the piperidinone 3a with sodium borohydride furnished piperidinol 5 stereoselectively with the arising hydroxyl group being oriented cis to the R-methyl substituent (95% yield, dr = >20:1, eq 3). Further stereoselective hydrogenation of 5 by the well-established method using Crabtree’s catalyst afforded tetrasubstituted piperidine 6 in 86% yield.15 The cross-coupling reaction of the stannyl-substituted dehydropiperidinone 3k with 4-iodoanisole produced 4-anisylpiperidine 7 (77%, 98% ee, eq 4), which was unavailable with regioselective control from unsymmetrical anisylphenylethyne. Upon treatment of 3g with DBU, p-toluenesulfinate was eliminated to give 4,5disubstituted 3-hydroxypyridine 8,3b which is the core structure of both pyridoxines and pyridinolines16 (eq 5).
In summary, we have described the nickel-catalyzed reaction of azetidin-3-ones that selectively insert a triple
a
Reaction conditions: 1.0 equiv of 1, 1.5 equiv of 2, 5 mol % Ni(cod)2, 10 mol % PPh3, toluene, 80 °C, 18 h unless otherwise noted. b Isolated yields. c 1.1 equiv of 2. d Rt, 15 h. e PCy3 was used instead of PPh3. f 60 °C, 15 h. Org. Lett., Vol. XX, No. XX, XXXX
(14) For disscussions on the regioselectivity of oxidative cyclization on nickel, see: (a) Miller, K. M.; Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130. (b) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342. (c) Sa-ei, K.; Montgomery, J. Org. Lett. 2006, 8, 4441. (d) Saito, N.; Katayama, T.; Sato, Y. Org. Lett. 2008, 10, 3829. (e) Malik, H. A.; Chaulagain, M. R.; Montgomery, J. Org. Lett. 2009, 11, 5734. C
bond into one of their carbon carbon bonds to furnish dehydropiperidinones. When combined with Seebach’s method for azetidinone synthesis, the present reaction provides a reliable synthetic pathway to enantiopure piperidines with various substituents including functionalized ones starting from R-amino acids. (15) The stereochemistry of 6 was assigned based on the premise that Crabtree’s catalyst hydrogenates a cyclohexenol derivative selectively from the side cis to the directing hydroxyl group: Crabtree, R. G.; Davis, M. W. J. Org. Chem. 1986, 51, 2655. (16) Fujimoto, D.; Moriguchi, T.; Ishida, T.; Hayashi, H. Biochem. Biophys. Res. Commun. 1978, 84, 52.
D
Acknowledgment. This work was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas “Molecular Activation Directed toward Straightforward Synthesis” and Grant-in-Aid for Scientific Research (B) from MEXT and The Asahi Glass Foundation. Supporting Information Available. Experimental procedures and spectral data for new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
